title: Heparin alters viral serpin, serp-1, anti-thrombolytic activity to anti-thrombotic activity.
abstract: Serine protease inhibitors (serpins) regulate coagulation and inflammation. Heparin, a glycosaminoglycan, is an important cofactor for modulation of the inhibitory function of mammalian serpins. The secreted myxoma viral serpin, Serp-1 exerts profound anti-inflammatory activity in a wide range of animal models. Serp-1 anti-inflammatory and anti-atherogenic activity is dependent upon inhibition of the uPA / uPA receptor thrombolytic complex. We demonstrate here that heparin binds to Serp-1 and enhances Serp-1 inhibition of thrombin, a human pro-thrombotic serine protease, in vitro, altering inhibitory activity to a more predominant anti-thrombotic activity. Heparin also facilitates the simultaneous thrombin-mediated cleavage of Serp-1 and prevents formation of a serpin-typical SDS-resistant complex, implying mutual neutralization of Serp-1 and thrombin. In a cell-based assay, heparin facilitates Serp-1 reversal of cellular activation by stabilizing cellular membrane fluidity in thrombin-activated monocytes. In conclusion, heparin and other GAGs serve as cofactors enhancing Serp-1 regulation of local thrombotic and inflammatory pathways.
authors.affiliation: Viron Therapeutics Inc., London, Ontario, Canada.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.forename: Heather
authors.initials: H
authors.lastname: Schneider
authors.forename: Andrew
authors.initials: A
authors.lastname: Peters
authors.forename: Colin
authors.initials: C
authors.lastname: Macaulay
authors.forename: Elaine
authors.initials: E
authors.lastname: King
authors.forename: Yunming
authors.initials: Y
authors.lastname: Sun
authors.forename: Liying
authors.initials: L
authors.lastname: Liu
authors.forename: Erbin
authors.initials: E
authors.lastname: Dai
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Davids
authors.forename: Grant
authors.initials: G
authors.lastname: McFadden
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lucas